Irinotecan hydrochloride, (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]-indolizino[1,2-b]quinolin-9-yl[1,4′-bipiperidine]-1′-carboxylate hydrochloride or 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin hydrochloride (CPT-11), having the formula I
is a camptothecin analog and topoisomerase I inhibitor. Its trihydrate form has been approved in 1996 in the United States for the treatment of colon cancer, but it is also of interest for treatment of other cancers, such as cancers of the lung, the stomach and the pancreas.
Irinotecan is usually prepared semisynthetically from natural camptothecin, which is extracted from a Chinese tree, Camptotheca acuminata. U.S. Pat. No. 4,604,463 describes several camptothecin derivatives, including irinotecan, its pharmaceutically acceptable salts and preparation thereof starting from natural camptothecin. U.S. Pat. No. 6,121,451 discloses intermediates and process for the synthesis of camptothecin derivatives, e.g. irinotecan hydrochloride, including synthetic route to starting material, 7-ethyl-10-hydroxy camptothecin.
Sawada et al., Chem. Pharm. Bull. 39(6), 1446-1454 (1991), describes the preparation of irinotecan hydrochloride trihydrate from natural camptothecin in five steps and about 20% of overall yield. Similar process is described also in U.S. Pat. No. 6,723,729. WO 03/074527 describes a new anhydrous polymorphic form of irinotecan hydrochloride, and its preparation. This polymorphic form is said to have improved solubility properties compared to the known trihydrate.
Now we have surprisingly found out that irinotecan can be produced in high yield and purity from 7-ethyl-10-hydroxy camptothecin and [1,4′]-bipiperidinyl-1′-carbonyl chloride or its hydrochloride, if the excess of [1,4′]-bipiperidinyl-1′-carbonyl chloride is eliminated after the reaction and the product is isolated by crystallization.